The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/ activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a metaanalysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice.
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Objective: To assess the economic impact of the introduction of bevacizumab and cetuximab, in 1st and 2nd line treatment of mCRC patients in Veneto region (North-East of Italy). Methods: A Markov state decision model was implemented to evaluate the cost impact of bevacizumab and cetuximab use in patients with mCRC for a lapse of time of three years in Veneto public hospitals. The Markov model expressed transition probabilities from three different states, comparing in addition the expected deaths and the monthly survival rates in treatment and no-treatment groups, along the lines of previously published studies. Results: The cost impact of bevacizumab administration in patients with mCRC accounted a mean value of 18268788 € within the first 6 months. Cetuximab therapy for those refractory to 1st line treatment, increased costs of almost 833340 € in the first 6 months, increasing in the following period due to a higher portion of patients switching from a stable status to a progressive one. Discussion: The cost impact of monoclonal antibodies on health expenses is very high. For a regional cohort like the Veneto's one, figure sets around 19000000 € in 6 months, when considering 1st and 2nd line treatment, reaching the level of 50000000 € within three years.
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Objective: To evaluate the impact of multitargeted tyrosine kinase inhibitors (TKI) considering 1st and 2nd line treatment for a full period of 3 years in the eligible patients of Veneto Region. Methods: A Markov state decision model was selected to evaluate the cost impact of sunitinib and sorafenib use for a lapse of time of three years in Veneto public hospitals, considering transition probabilities from three different states and by comparing the expected deaths and the monthly survival rates in treatment and no-treatment groups. Results: From the initial cohort of 357 patients eligible for sunitinib treatment, stable ones (139) were considered in order to evaluate the impact of the multitargeted agent on overall progression of the disease. Results showed that a smaller portion of patients receiving sunitinib transited from a stable to a progressive state, with respect to the patients who were not receiving sunitinib. The cost of 6 months treatment with sunitinib reached a median value of 2532666€, increasing till 3607807€, as cumulative amount at 12 months. Costs after the 1st year flattened around the same figure (3800000€) due to the transition towards death or 2nd line treatments. Discussion: the costs of the first 6 months therapy with sunitinib have a very high impact on public health expenses in the Regione Veneto. 2nd line treatment with sorafenib instead increased overall expenses of a reduced proportion, due to the small proportion of patients undergoing this treatment and the relative inferior cost of the drug. Conclusion: From what came out from our simulated model on costs borne by the SSN for the treatment of patients with mRCC, we can conclude that they are effective on the progression of the disease the greatest impact being the cost for the 1st line pharmacological treatment.
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